Assistant Clinical Professor Neonatal Fever Shabnam Zargar, MD, FAAP Assistant Clinical Professor Pediatrics UCR School of Medicine

Neonatal Fever A 15 day old infant presents to the ED with a temperature of 38.4 degrees Celsius (101.4 Fahrenheit). What to do next and why?

Neonatal fever What is neonatal fever? Temperature of 38 degrees Celsius (100.4 Fahrenheit) in infants 0-28 days of life. Rectal temperature recommended Some sources consider neonate <30 days old – most pediatric sources use <30 days, Cincinnati uses 28 days

Neonatal Fever Why is neonatal fever important? Febrile neonates are at high risk for serious infection (SI) or serious bacterial infection (SBI) because of increased susceptibility to infections, difficulty with clinical examination, and poor outcomes if not diagnosed or treated properly A neonate cannot tell you what is wrong

Neonatal Fever Differential Diagnoses: Meningitis bacterial or viral Bacterial – GBS, E. coli, Listeria Viral – Enterovirus HSV infections localized or disseminated infections UTI E. coli, Enterococcus Bacteremia Sepsis Cellulitis Abscess Osteomyelitis Septic arthritis Viral Localized HSV – encephalitis w/wo skin involvement or skin, eye, and mouth Disseminated – hepatitis, pneumonitis, or DIC w/wo encephalitis or skin disease

Neonatal Fever Most common etiology Viral illness Viral Bacterial etiologies: Most common – UTI UTI Followed by: Meningitis Bacteremia/Sepsis Sepsis or bacteremia Abscess or cellulitis Pneumonia Meningitis Approximately 12%-28% of neonates presenting to a pediatric ED with fever have a SBI - bacteremia, gastroenteritis, cellulitis, osteomyelitis, septic arthritis, meningitis, pneumonia, and UTI (Cincinnati) Neonates with viral etiology are less likely to have a SBI If viral illness, 4.2% have SBI vs 12.3% without viral illness

Neonatal Fever History to obtain: Febrile infants may have few symptoms to guide diagnosis and management History to obtain: Fever? How high? How was temperature measured? Last anti-pyretic use? Change in feeding? Irritability or lethargy? Seizures? Change in cry? URI symptoms? Difficulty breathing? Swelling of joints or skin changes? Sick contacts? Vomiting or diarrhea? Skin changes – rashes/vesicles/jaundice

Neonatal Fever Physical exam Gen: Mentation? HEENT: Anterior fontanelle – bulging? Eyes – Cellulitis/conjunctivitis? Ears – otitis? Nose – congestion? Rhinorrhea? Throat – weak/high pitched cry? Cough? Neck: Swelling? Neck stiffness is a sign in older children Lungs: Retractions? Crackles? Ronchi? CVS: Murmur? Tachycardia? Capillary refill? Pulses? Abdomen: Omphalitis? GU: Circumcised? Skin: Cellulitis/Abscess? Rash? MSK: Joint swelling? Neuro: Mentation? Irritable? Lethargic? Omphalitis – polymicrobial – S. aureus, GAS, E. coli, K. pneumoniae, Proteus mirabilis Brudzinski sign – flexion of the neck elicits reflex flexion of the hips Kernig sign – extension of a flexed knee is painful

Neonatal Fever Diagnosis Laboratory: Full sepsis workup CBC with manual differential Blood culture UA with microanalysis (urethral catheterization) Urine Culture CSF studies – tube 1 culture, tube 2 protein and glucose, tube 3 cell count and differential, tube 4 – HSV PCR if HSV encephalomengitis suggested If CSF pleocytosis, add enterovirus PCR CXR if symptomatic Stool culture if diarrhea present *Ok to delay LP if patient unstable, do administer antibiotics! *Full septic workup still recommended in neonates with symptoms of bronchiolitis CXR recs differ from AAFP

Neonatal Fever Values CBC with manual differential: Normal WBC 5,000-15,000 per mm3 WBC < 5,000 or >15,000 per mm3 or ANC >10,000 per mm3 have increased risk of SBI CSF: Low risk of meningitis: <20WBC/mm3 High risk of meningitis: >20WBC/mm3 Other values: High protein >120mg/dL and low glucose <40mg/dL Urinalysis: WBC < 10/mm3, negative LE and nitrites Harriet Lane has values

Neonatal Fever Management Admit to inpatient pending culture results IV antibiotics to cover common organisms – empirical treatment should be given immediately after cultures obtained Ampicillin and gentamicin Ampicillin and 3rd generation cephalosporin -Cefotaxime preferred over ceftriaxone *All neonates should be given a single dose of ampicillin and cefotaxime immediately after cultures are obtained IV antiviral Acyclovir should be started on all neonates who have pending CSF HSV PCR studies Clinical prediction models have not been able to accurately predict SBIs in neonates so common practice remains for hospitalization for sepsis evaluation and IV antibiotics (Fielding-Singh et al.)

Neonatal fever Antibiotics Ampicillin Gentamicin Cefotaxime covers Enterococcus and Listeria, also Streptococcus/gram positives Gentamicin covers gram negatives, crosses blood brain barrier Cefotaxime covers gram negatives (rising resistance of E. coli to Ampicillin), crosses blood brain barrier

Neonatal Fever All febrile neonates ≤ 28 days of age should be hospitalized, undergo a full sepsis evaluation, and receive empirical IV antibiotics

Neonatal fever Pre-treated CSF: Can add real time PCR and DNA sequencing for bacterial rRNA if pleocytosis is present and there is a concern for meningitis

Neonatal Fever HSV in neonates Comprehensive testing required Surface swabs sent for HSV culture from nasopharynx, conjunctivae, and anus CSF for HSV PCR Blood for HSV PCR Vesicle fluid for HSV PCR – if rash present CBC with differential, BUN, creatinine, AST and ALT Nelson Textbook of Pediatrics: Expert Consult

Neonatal Fever HSV in neonates Greatest risk in neonates born vaginally to mothers with risk factors for primary maternal HSV infection Clinical features: severe illness, hypothermia, lethargy, seizures, HSM, postnatal HSV contact, vesicular rash, conjunctivitis, interstitial pneumonitis Laboratory features: Thrombocytopenia, elevated transaminases, CSF pleocytosis >20 WBC/mm3 with negative gram stain *If suspicion for HSV infection or HSV PCR performed on CSF, begin acyclovir with empiric antibiotics What are some of the risk factors? Mom’s sexual partners have history of oral or genital HSV, new sexual partner in pregnancy, sores in vagina during pregnancy, urinary retention, hx of frequent yeast infections, receipt of oral sex during last half of pregnancy from partner with hx of cold sores Merck Manual Professional Version

Neonatal Fever How long to admit for? Standard length of hospitalization: 48 hours – “48 hour rule out sepsis” Studies are being performed to determine if 48 hours of hospitalization is really needed Recent studies have also looked at low risk criteria for treating febrile neonates less conservatively but concluded that low risk criteria are not sufficiently reliable to exclude SBIs in febrile neonates Standard has been to admit for 48 hours – why? Because at 48 hours, there is greatest chance of negative cultures being truly negative. Some centers changing to 36 hours and even 24 hours.

Neonatal Fever One study from Hospital Pediatrics (Fielding-Singh et al.): Objective: To determine the risk of a positive, pathogenic bacterial culture of blood or CSF in infants ≤ 30 days beyond 24 hours after collection Methods: retrospective review of 1,145 infants ≤ 30 days with blood or CSF cultures drawn at Santa Clara Valley Medical Center in San Jose, CA from 1999-2010. High risk infants had WBC <5,000 or >15,000 per microliter, bands >1,500 per microliter, or abnormal UA Results: 1,876 blood and CSF cultures were identified. 79% were hospitalized and of those hospitalized, 45% were for fever without a source. 2.7% had pathogenic cultures and 0.5% had a time to notification >24 hours (not statistically significant), of those 0.5%, all had fever without source and high-risk criteria. No low-risk criteria patient had a time to notification >24 hours. 1.8% of high risk patients had growth 24-48 hours. Conclusion: Low-risk infants hospitalized for fever without source may not need hospitalization for 48 hours to rule out bacteremia or meningitis Non-ICU patients. Time to notification = time from sample collection to notification of medical staff. Time to notification for urine not available because medical staff not contacted directly with positive UAs. Those with TTN >24 hours had E. coli, Enterococcus, GBS and S. aureus bacteremia. Low risk = well-appearing, previously healthy, no focal infection, normal UA and WBC, nml CXR and stool smear

Neonatal fever Study continued: Mean and median time to notification 24.5 ± 17.1 and 19 hours for pathogens and 45.3 ± 30.7 and 35.8 hours for contaminants, respectively

Neonatal Fever Previous studies: Time to positivity of blood and CSF cultures in neonates suggest that 48 hours is necessary to identify >95% of cases, however, these studies included infants in the ICU where CoNS and yeast cultured from central lines take time to grow (Fielding et al.)

Neonatal Fever Approximately 90% of bacterial pathogens are identified within the first 24 hours of incubation (Byington et al.) Infants 0-6 months of age: Blood cultures: Mean time to positivity for true pathogens is ~17.5 hours Urine and CSF: Median time to positivity are 16 and 18 hours, respectively

Seattle Children’s recommends this Neonatal Fever Consider discharge at 24 hours if bacterial cultures negative and viral studies positive (excluding HSV) AND well-appearing Patients with bronchiolitis or other viral infections are at lower risk of SBI Seattle Children’s recommends this

Neonatal Fever Discharge criteria: Well-appearing Tolerating PO Follow up available within 48-72 hours Family and primary care team agree with plan Cultures negative What do you think would be some discharge criteria?

Neonatal Fever If a neonate presents with fever to your clinic -Send to the ED If you receive a call from a mom stating her neonate has a fever If you are working in the ED and have a neonate with fever -Perform full septic workup, give first dose of ampicillin and cefotaxime, and admit to inpatient If you are the admitting inpatient team – continue/begin empirical antibiotics, making sure urine, blood, and CSF cultures have been drawn (if LP not successful and patient appears meningitic – do not delay antibiotics), and observe 48 hours pending cultures real time PCR and DNA sequencing for bacterial rRNA

Neonatal Fever Side note: Neonates with meningitis need to be admitted to a hospital with pediatrics ID and PICU -Complications – seizures, empyema, elevated ICP -BAER and ophthalmology exam

Neonatal Fever Possible QI project? Develop a standardization pathway of management of neonatal fever in our institution based on clinical evidence Standardization improves medical care! Discuss neonatal age as being less than 28 or 30 days and decide length of hospitalization

References Bishop, Julianne, and S. Heath Ackley. Clinical Standard Pathway: Neonatal Fever. Project Owners, Aug. 2013. Web. 20 July 2015. https://www.seattlechildrens.org/pdf/neonatal-fever-learning-module.pdf. Byington, Carrie L., F. Rene Enriquez, Charles Hoff, Richard Tuohy, E. William Taggart, David R. Hillyard, Karen C. Carroll, and John C. Christenson. "Serious Bacterial Infections in Febrile Infants 1 to 90 Days Old With and Without Viral Infections." Pediatrics 113.6 (2004): 1662-666. Caserta, Mary T. "Neonatal Herpes Simplex Virus (HSV) Infection - Pediatrics." Merck Manuals Professional Edition. Merck Sharp & Dohme Corp, May 2013. http://www.merckmanuals.com/professional/pediatrics/infections-in-neonates/neonatal-herpes-simplex-virus-hsv-infection. Accessed 24 July 2015. Cincinnati Children's Hospital Medical Center. Evidence-based care guideline for fever of uncertain source in infants 60 days of age or less. October 27, 2010. http://www.cincinnatichildrens.org/svc/alpha/h/health-policy/ev-based/default.htm. Accessed July 20, 2015 Fielding-Singh, Vikram, David K. Hong, Stephen J. Harris, John R. Hamilton, and Alan R. Schroeder. "Ruling Out Bacteremia and Bacterial Meningitis in Infants Less Than One Month Of Age: Is 48 Hours of Hospitalization Necessary?" Hospital Pediatrics 3.4 (2013): 355-61. Web. Hamilton, Jennifer L., and Sony P. John. "Evaluation of Fever in Infants and Young Children." American Family Physician (2013): http://www.aafp.org/afp/2013/0215/p254.html. Accessed July 20, 2015. Kliegman, Robert M., Bonita M.D. Stanton, Joseph St. Geme, and Nina F. Schor. Nelson's Textbook of Pediatrics: Expert Consult. 20th ed. Philadelphia: Elsevier, 2016. Jain, Shabnam, John Cheng, Elizabeth R. Alpern, Cary Thurm, Lisa Schroeder, Kelly Black, Angela M. Ellison, Kimberly Stone, and Evaline A. Alessandrini. "Management of Febrile Neonates in US Pediatric Emergency Departments." Pediatrics 133.2 (2014): 187-95.